Enhanced Treatment in Severe-Critical COVID-19 With Tocilizumab, Remdesivir, Dexamethasone: A Jordanian Cohort Study

Background: Several medications have been proposed to manage COVID-19, with controversial data regarding their clinical benefits. We aimed to investigate the clinical efficacy of using remdesivir (RDV) with and without tocilizumab (TCZ) and standard therapy in treating severe COVID-19. Methods: This retrospective cohort study was conducted in a Jordanian tertiary hospital (September 26th, 2020 - August 28th, 2021) and included adult COVID-19 patients requiring oxygen support. Patients were categorized into three groups based on treatment: TCZ+RDV and standard therapy; RDV and standard therapy; and standard therapy alone, which included dexamethasone, vitamins, anticoagulants, and ceftriaxone. Results: Of 1,556 screened, 1,244 patients (mean age 62.33, 60.8% men) were included. Distribution was 106 in TCZ+RDV, 520 in RDV, and 618 in standard therapy. No significant differences were observed in age, gender, or BMI. Mortality was lowest in TCZ+RDV (32.1%), followed by RDV (40.6%) and standard therapy (47.1%) (p=0.005). Among ICU patients, TCZ+RDV showed significantly lower mortality (51.1%) compared to RDV (75%) and standard therapy (85.8%) (p<0.001). The ICU stays and invasive mandatory ventilation (IMV) durations were significantly shorter with TCZ+RDV (4.30 and 2.69 days, respectively) compared to RDV (7.61 and 4.52 days) and standard therapy (7.98 and 5.32 days) (p<0.001 for ICU stays, p=0.025 for IMV durations). Conclusions: Combining TCZ, RDV, and dexamethasone shows promise in reducing mortality and ICU/IMV duration for severe COVID-19.


Study design, patients, and ethical considerations
This is a retrospective cohort study conducted at the King Abdullah University Hospital (KAUH), the largest hospital in the north of Jordan, which serves a population exceeding two million and has a capacity of 750 beds [5].It was assigned by the government as a COVID-19 referral center.The study spanned between September 26th, 2020, and August 28th, 2021 including patients hospitalized with COVID-19 and required oxygen support at any time during their hospitalization.This timeframe was not predetermined, it represents the time between the onset of the first COVID-19 peak in Jordan and the initiation of data collection [50][51][52].The diagnosis of COVID-19 was confirmed by reverse-transcriptase polymerase chain reaction (PCR) detection of SARS-CoV-2 RNA in the nasopharyngeal swab.Inclusion criteria included hospitalized COVID-19 patients who were 18 years or older; had evidence of pneumonia defined as dyspnea, orthopnea, paroxysmal nocturnal dyspnea (PND), or radiologic findings of lung infiltrates; had hypoxia (SpO2 <94%) on room air; and need oxygen support of at least 6 L/min during hospitalization.On the other hand, pregnant women, mild/asymptomatic cases, and those not meeting inclusion criteria were excluded.
All procedures conducted in this study were reviewed and ethically approved by the Institutional Review Board (IRB) committee at Jordan University of Science and Technology, Irbid, Jordan (IRB number: 27/137/2021), adhering to the 1975 Helsinki Declaration, as revised in 2008, its later amendments, and comparable ethical standards.Written informed consent for participation was obtained from the patients, and the file containing the link of the patient-specific code with their name and hospital file number was locked and password protected.Thus, the patients' information confidentiality was guaranteed, and the data analysis was conducted on the de-identified database.Upon admission, all hospitalized COVID-19 patients have received the standard COVID-19 therapy, including dexamethasone, vitamin D3, vitamin C, paracetamol, proton pump inhibitors (PPIs), lowmolecular-weight heparin (LMWH), and ceftriaxone.Systemic dexamethasone was administered intravenously (IV) at a daily dose of six mg for up to 10 days or until the patient's discharge or death, whichever occurred first.Vitamin D3 and vitamin C were administered orally at daily doses of 5000 IU and 1000 mg, respectively.Paracetamol was administered IV or orally in divided doses up to 4 grams per 24 hours, with at least four hours between each dosage.The recommended PPI daily dosage all over the patient's hospitalization was either 40 mg of esomeprazole given by IV injection, or 30 grams of lansoprazole received orally.Also, prophylactic, or therapeutic doses of subcutaneous enoxaparin and 1 gram of IV ceftriaxone were given daily to all patients unless contraindicated.Other antibiotics, including azithromycin, levofloxacin, carbapenems, and piperacillin-tazobactam, were given as needed for superimposed nosocomial bacterial infections following the judgment of the attending physicians.

Management of COVID-19 patients and study groups
RDV was given IV with a single loading dose of 200 mg, followed by 100 mg once daily for the next five days or until hospital discharge or death, whichever occurred first.RDV therapy was extended to 10 days If the patient was mechanically ventilated and did not show clinical improvement.On October 22nd, 2020, the USFDA approved RDV use in treating COVID-19 patients requiring hospitalization and oxygenation [22].Accordingly, the Ministry of Health (MOH) in Jordan started to import and get supplied by this medication to provide for free to severe and critical hospitalized cases requiring respiratory support with no RDV contraindications.
TCZ was administered IV with a single dose of 8 mg per kilogram of the patient's body weight, not exceeding 800 mg.A second dose could follow at least 12 hours in patients demonstrating clinical deterioration of COVID-19 signs and symptoms (e.g., increased respiratory support requirement) [53].TCZ has not received the USFDA EUA approval for COVID-19 treatment until June 24th, 2021 [24].Thus, TZC was given as rescue therapy for clinically worsening hypoxic adult patients having radiologic lung infiltrates and elevated inflammatory markers, with no drug contraindications.Consultation with the infectious disease team was required to ensure that patients were eligible for TCZ therapy based on COVID-19 severity criteria and drug contraindications.Moreover, written, or oral informed consent was required to obtain from the patients themselves or their legally authorized representatives.
The enrolled patients were categorized based on the COVID-19 therapy regimen into three groups.The TCZ+RDV group compromised the patients who received the combination of TCZ plus RDV and standard COVID-19 therapy, while those treated with RDV plus standard COVID-19 therapy were classified as the RDV group.Lastly, the patients who received the standard COVID-19 therapy, neither TCZ nor RDV, were categorized as the Standard of Care (SOC) group.

Data collection and clinical evaluations
We reviewed the electronic medical charts of the enrolled patients; socio-demographic and clinical data were retrospectively collected from the patient's electronic medical records, including age, gender, weight, height, body mass index (BMI), cigarette smoking history, and comorbidities.BMI was categorized according to the conventional WHO classification into normal weight (18.5-24.9kg/m2), overweight (25.0-29.9kg/m2), and obese (≥30.0 kg/m2) [58].The comorbidities were identified based on the International Classification of Diseases (ICD) criteria [59].The baseline clinical status of the enrolled patients at the time of admission was reviewed and abstracted from the electronic medical records, including vital signs, radiological findings, oxygen support categories, and blood laboratory values.The laboratory values were interpreted following the local reference values of KAUH.The patients were classified based on the illness severity at admission time into moderate, severe, or critical cases following the NIH classification of the clinical spectrum of SARS-CoV-2 infection [60].
The hospitalization details, including admission date, received therapies, the highest level of care, complications and serious events development, end-result of admission, discharge/death date, and oxygen support categories during hospitalization and their durations, were also obtained from the patient's medical records.The oxygen supports were grouped into four categories: low-flow oxygen, high-flow oxygen, noninvasive ventilation (NIV), and invasive mechanical ventilation (IMV) [61].The NIV support measures comprised continuous positive airway pressure (CPAP) and bi-level positive airway pressure (BiPAP).

Statistical analysis
The SPSS Statistics Windows software, version 25.0 (IBM Corp., Armonk, NY, USA), was used for data processing and analysis.Descriptive statistics, including frequencies and percentages, were calculated for the categorical variables.While continuous variables were presented as mean (standard deviation, SD).The univariate analyses were conducted to assess the differences between the three therapy groups using a Chisquare or Fisher's exact test for categorical variables and one-way ANOVA for continuous variables.Regarding the primary and secondary clinical outcomes, we report the relative risk (RR) of mortality and oxygen support categories among the patients who received TCZ plus RDV and standard COVID-19 therapy compared with the patients of the RDV group.Similarly, the mean difference between the two groups of TCZ+RDV and RDV therapies was calculated and reported for the duration of hospitalization, ICU stays, and oxygen support categories.Also, their 95% confidence intervals (95% CI) and p-values were reported.
The Kaplan-Meier test was conducted to estimate the survival probability of the three therapy groups over the hospitalization duration, divided by seven-day time intervals.Also, we assessed the differences in the survival distributions between the therapy groups using the log-rank test.The estimated mean (SD) time to death after admission was calculated for each therapy arm using Kaplan-Meier analysis.Patients who were discharged alive from the hospital were censored.Cox proportional analyses were then conducted to calculate the hazard ratios (HR) for death among patients of the TCZ+RDV and RDV groups compared to patients of the SOC group.
A binary logistic regression analysis was also used to assess the predictors of in-hospital mortality among hospitalized COVID-19 patients.The dependent variable was the end-point of patient hospitalization, which was collapsed into "0 = discharge alive" and "1 = death".Model selection using the stepwise backward approach with a cutoff p-value of 0.2 was used to select the final, most parsimonious model.The therapy regimens, age, gender, obesity, smoking status, severity on admission, radiological findings on admission, comorbidities of hypertension, diabetes mellitus (DM), ischemic heart disease (IHD), asthma, chronic obstructive pulmonary disease (COPD), chronic kidney disease (CKD), being on hemodialysis, heart failure, atrial fibrillation, cerebrovascular accident (CVA), gout, hypothyroidism, active cancer, anemia, and being immunocompromised, vasopressors use, the highest level of care (ICU or regular floor), and oxygen support categories during hospitalization were included as independent explanatory variables.The variables in the last model were checked for multicollinearity using the variance inflation factor (VIF).Adjusted odds ratios (OR) and their 95% CIs were reported.Statistical significance was considered at a p-value of ≤ 0.05.

Baseline characteristics of the patients
Overall, 1,556 laboratory-confirmed SARS-CoV-2-infected consecutive patients were admitted to KAUH during the study period.Excluded patients comprised 139 younger than 18 years, pregnant women, asymptomatic, or mildly infected.Also, 173 patients were excluded as they did not require oxygen support during hospitalization.Thus, this study included 1,244 COVID-19 patients based on the inclusion and exclusion criteria (Figure 1).

FIGURE 1: The flow chart of the study Participants.
The mean (SD) age of participants was 62.33 (13.83), and 756 (60.8%) were men.Moreover, their mean (SD) BMI was 30.56 (6.00), and 329 (26.6%) were ex-or current smokers.According to COVID-19 therapy, 106 (8.5%) patients received TCZ + RDV + standard COVID-19 therapy, 520 (41.8%) patients received RDV + standard COVID-19 therapy, while the SOC group consisted of 618 (49.7%) patients.The mean (SD) followup time was 11.53 (8.51) days, ranging from 1 to 57 days.The age, gender, and BMI were equally represented in the three therapy groups, with no statistically significant differences observed between the groups (p>0.05 for each).However, smoking status differed between the three therapy groups as the percentage of ex-and current smokers was significantly higher among the SOC cohort (30.3%) than RDV (23.3%) and TCZ+RDV groups (19.8%) (p=0.008).There were no statistically significant differences in the comorbidities between the three groups except for DM, CKD, patients on hemodialysis, and benign prostatic hyperplasia (BPH).

Clinical features and laboratory findings at the time of admission
The summary of the baseline vital signs, radiological findings, severity, type of oxygen support, and laboratory findings on the admission and their differences among the therapy groups are illustrated in Table 2.The prevalence rates of hypoxia were higher among the patients of the RDV and TCZ+RDV groups (90.6% and 89.6%, respectively) than in the patients assigned to SOC therapy (78.6%) (p<0.001).However, there were no statistically significant differences between the three therapy groups in fever, tachycardia, and tachypnea percentages (p>0.05 for each).The chest radiography at the time of admission showed bilateral infiltration among most participants (92.8%), with no statistically significant differences between the three groups (p=0.218).The vast majority of the participants (89.1%) were severe or critical upon admission, and 92.1% needed oxygen support at admission, with low-flow oxygenation being the most prevalent respiratory support (74.8%).Statistically significant higher percentages of RDV and TCZ+RDV groups' patients were categorized as critical cases on admission (70.0% and 67.0%, respectively) in comparison with 54.9% among the SOC patients (p<0.001).The three therapy groups showed insignificant differences in the measurements of baseline laboratory parameters except for hemoglobin, potassium, and albumin mean values (

Management, oxygenation, and complications during hospitalization
All COVID-19 patients in this study have received systemic corticosteroids, and the vast majority (97.7%) have received at least one antibiotic, including azithromycin, levofloxacin, carbapenems, or piperacillin.About one-third of the patients needed vasopressors during their hospitalization.Table 3 shows the COVID-19 patients' management, hospitalization site, and complications during hospitalization.There were no statistically significant differences between the three groups in the received medications except for carbapenems, piperacillin, levofloxacin, and aspirin.The percentages of patients who received carbapenems and piperacillin were higher among the TCZ+RDV group (43.4% and 64.2%, respectively) than in the other groups.On the other hand, significantly lower percentages of the TCZ+RDV patients received levofloxacin and aspirin (86.6% and 37.7%, respectively) than patients of the other groups.More than half of the participants (56.9%) were on the regular floor, while 43.1% required intensive care unit (ICU) admission, with no significant differences between the therapy groups in the highest level of care (p=0.172).The most prevalent complication during hospitalization was acute kidney injury (AKI) (18.6%).The development of complications was similar among the three therapy groups except for AKI, myocardial infarction (MI), emphysema, and venous thromboembolism.The AKI and MI events were significantly more prevalent among the SOC patients than in the patients of the other groups.In contrast, emphysema and venous thromboembolism were significantly more common in the TCZ+RDV group than in other groups (Table 3).4).

Primary outcomes
The survival plots for the three therapy groups are shown in Figure 2. Survival analysis using the Kaplan-Meier test showed a significantly lower risk of mortality and a higher cumulative survival proportion among patients treated with the combination of TCZ plus RDV and standard COVID-19 therapy than in the other therapy arms (log-rank test; χ2(1) = 22.714, p<0.001) (Figure 2).The estimated mean (SD) time to death after admission was 27.96 (1.83) in the TCZ+RDV group compared to 20.67 (0.85) in the RDV group and 19.90 (0.99) in the SOC group (p<0.001).Compared to the SOC group, the HR for death in the TCZ+RDV group was 0.434 (95% CI 0.304−0.619,p<0.001), while the HR was 0.825 (95% CI 0.690−0.985,p=0.033) in the RDV group.

FIGURE 2: Kaplan-Meier survival analysis plot.
This plot illustrates the patients' survival probability beyond the time from hospital admission to death/discharge, with a comparison between the study groups using the log-rank test.Being alive on the day of discharge was considered a censored event.

Secondary outcomes
Overall, the mean (SD) duration of hospitalization and ICU stay in the whole cohort were 11.53 (8.51)  Regarding the oxygen support duration, there were no significant differences when evaluating the three   retrospective nature of this study and being a single-center study limit the generalization of our findings and could not prove causality-effect associations.However, the cohort design of the study comparing different COVID-19 therapy regimens could provide strong association evidence for the clinical benefits of the combination therapy.Second, the patients who received TCZ had already received RDV.Thus, we could not determine which medication was superior to the other.Third, the specific timing of TCZ administration during hospitalization and its timing in the context of the disease course and other COVID-19 drugs was not specified.This limitation could be attributed to the fact that TCZ was administered as the last option to selected patients based on clinical and contextual factors due to its high cost, unavailability in our hospital, and not being approved by the USFDA during the study period.Fourth, there were differences between the three study groups in the proportions of receiving carbapenems, piperacillin, and levofloxacin during hospitalization.Thus, we could not rule out the potential effects of these antibiotics on the outcomes in our cohort.However, previous studies comparing survivors with non-survivors among COVID-19 patients suggested no clinical benefits of antibiotic therapy on the mortality rates [7,[68][69][70].Finally, this study did not investigate the safety profile and the best timing for administering the COVID-19 medications.However, these aspects were not part of our study objectives.Future studies are invited to investigate and evaluate the safety issues of this combination therapy.

Conclusions
We concluded that the triple therapy comprising TCZ, RDV, and standard therapy demonstrates reasonable clinical efficacy in treating severe SARS-CoV-2-infected hospitalized patients, reflected by significant survival benefits, reduced all-cause in-hospital and ICU mortality rates at days 14, 28, and hospitalization end-point, as well as shorter durations of ICU stays and all-cause support.Also, the study findings elucidated the added clinical value of TCZ to the RDV and dexamethasone in achieving favorable survival outcomes by day 14 of hospitalization and for ICU admitted patients and in accomplishing quicker ICU recovery with decreased duration of IMV support.
Our study's clinical evidence-based observations correspond with NIH, WHO, and USFDA guidelines, recommending the potential combination use of COVID-19 drugs for severe-critical cases.While overall hospital stay length and respiratory support needs did not show significant improvement with TCZ, RDV, and dexamethasone therapy, this may be attributed to the severity of cases in this therapy arm and our center's TCZ administration approach.Nonetheless, patients receiving this combination therapy showed shorter and minimal use of invasive ventilation compared to other regimens.Further trials are needed to validate the efficacy and safety profile of combined TCZ, RDV, and dexamethasone therapy, and identify optimal administration timings.Physicians are encouraged to stay updated with the latest evidence on COVID-19 therapy strategies to ensure patient safety and survival.
financial support was received from any organization for the submitted work.Financial relationships: All authors have declared that they have no financial relationships at present or within the previous three years with any organizations that might have an interest in the submitted work.Other relationships: All authors have declared that there are no other relationships or activities that could appear to have influenced the submitted work.

Table 1
summarizes the baseline sociodemographic characteristics and comorbidities of the included COVID-19 hospitalized patients.

Table 4
summarizes the clinical primary and secondary outcomes of the treated patients.Overall, 536 patients died (43.1%) in our cohort.The lowest all-cause in-hospital mortality rate was among patients assigned to receive the combination of TCZ, RDV, and standard COVID-19 therapy (32.1%), whereas it was 40.6% in the RDV group, and the highest in-hospital mortality rate was 47.1% within the SOC group (p=0.005).On day 14, the in-hospital mortality rates among the TCZ+RDV group, RDV group, and SOC group were 16.0%, 29.2%, and 34.5%, respectively (p<0.001).By day 28, 32 (30.2%) patients died in the TCZ+RDV group compared to 204 (39.2%) in the RDV group and 277 (44.8%) in the SOC group (p=0.002).Among the ICU admitted patients, 421 (78.5%) died.A considerably lower ICU mortality rate was reported among the TCZ+RDV group (51.1%) compared to the RDV group (75.0%) and those who did not take TCZ or RDV medications (85.8%) (p<0.001).

Table 5
illustrates the significant predictors for in-hospital mortality using binary logistic regression analysis.The combination therapy of TCZ plus RDV and standard COVID-19 therapy was associated with the lowest odds of in-hospital mortality (adjusted OR 0.057, 95% CI 0.022−0.150,p=0.007).Also, the RDV plus standard COVID-19 therapy was associated with a double-decreased odd of death compared to SOC (adjusted OR 0.506, 95% CI 0.309−0.829,p=0.007).On the other hand, the use of vasopressors, IMV, and NIV were independent risk factors of in-hospital mortality with the highest odds ratios among the studied parameters (p<0.001 for each).Moreover, ICU admission, renal failure, CVA history, and hypertension were also identified as significant predictors of in-hospital mortality among hospitalized COVID-19 patients.Also, the current smokers had double odds of mortality compared to the nonsmokers (adjusted OR 1.919, 95%CI 1.020−3.610,p=0.043).The model showed that an age rise by one year would increase the mortality probability by 1.062 (95%CI 1.042−1.083,p<0.001).